The existing methods of drug delivery to the inner ear such as the deposition of therapeutic agents in the middle ear on the round window membrane (RWM) by intratympanic injections are not very effective. Systemic corticosteroid therapy is also problematic due to systemic side effects. Intracochlear injections provide more precise dosing but are not long lasting that effective treatments may require multiple dosing, this increasing the risks of damaging the cochlear. Other methods of intratympanic and intracochlear delivery such as the use of catheters, pumps (e.g., osmotic pump, infusion pump), injectors, and drug coated implants are complicated due to the complex mechanics involved. Because of the challenges in inner ear drug delivery, many inner ear disorders cannot be treated effectively. With the recent advances in drug discovery of new chemical entities and new knowledge in hearing disorders, there is an unmet need to effectively deliver drugs to the inner ear. The objective of the present project is to develop a robust, long- lasting, and safe method of drug delivery to the inner ear using a sustained release temperature sensitive gel and controlled delivery using iontophoresis. A temperature sensitive gel system that is a liquid at room temperature to conform on the round window niche and solidify at body temperature will first be evaluated to provide sustained baseline inner ear delivery via the RWM. This gel will be placed in the middle ear by intratympanic injection, and has a significant advantage over the conventional intratympanic injection method. To enhance drug delivery from the gel to the inner ear on an as-needed basis, iontophoresis will be used. In addition to enhance drug delivery, iontophoresis will also be used to replenish the drug in the gel when needed over the treatment. Iontophoresis will be performed with the electrode placed in the external ear in electrical contact with the tympanic membrane, which in turn is in contact with the gel system in the middle ear, with the gel in the middle ear serves as both the drug depot and a conduit of the electric current from the electrode in the external ear to the RWM. The ultimate goal of the project is to develop a drug delivery platform for inner ear delivery that is effective and well tolerated while easy to administer. PUBLIC HEALTH RELEVANCE: There is an unmet need to develop a robust, long lasting, and safe drug delivery method for the inner ear to take advantage of the new knowledge in the treatment of hearing disorders. The present project will begin the development of a drug delivery method using a temperature sensitive hydrogel that is a solution at room temperature but gel in the middle ear for sustained drug delivery to the inner ear. Iontophoresis will then be developed that can be applied noninvasively to the external ear for controlled drug delivery from this hydrogel on an as-needed basis. It is believed that this method can allow convenient and safe treatment of inner ear diseases.